Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions
Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions
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DOI：
10.1172/jci200411548
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发表时间：
2004-01-01
影响因子：
15.9
通讯作者：
Stabler, SP
中科院分区：
文献类型：
--
作者：
Antony, AC;Tang, YS;Stabler, SP
在许多恶性和正常人类细胞中，叶酸的细胞获取由叶酸受体（FR）介导。虽然FR在叶酸缺乏时上调，在叶酸补充后下调，但这种关系的机制基础尚不清楚。以前，我们证明了在FR mRNA的5 '-非翻译区的18个碱基的顺式元件和cybidopsis转因子（异质核核糖核蛋白El [hnRNP E1]）的相互作用是FR合成的关键。然而，控制这种相互作用的分子机制，特别是在FR调节和叶酸状态的背景下，仍然不清楚。人宫颈癌细胞显示出逐渐增加的上调FR后，叶酸-充满细胞转移到低叶酸培养基，没有成比例的上升FR mRNA或上升hnRNP El。翻译FR上调伴随着逐步积累的代谢产物同型半胱氨酸内培养的细胞，刺激相互作用的FR mRNA顺式元件和hnRNP E 1以及FR的生物合成中的剂量依赖性的方式。叶酸缺乏的突然逆转也导致同型半胱氨酸和FR生物合成的快速平行减少到叶酸充足细胞中观察到的水平。总的来说，这些结果表明，同型半胱氨酸是FR的翻译上调的关键调制器，并建立干扰叶酸代谢和协调上调FR之间的联系。
Cellular acquisition of folate is mediated by folate receptors (FRs) in many malignant and normal human cells. Although FRs are upregulated in folate deficiency and downregulated following folate repletion, the mechanistic basis for this relationship is unclear. Previously we demonstrated that interaction of an 18-base cis-element in the 5'-untranslated region of FR mRNA and a cystolic transfactor (heterogeneous nuclear ribonucleoprotein El [hnRNP E1]) is critical for FR synthesis. However, the molecular mechanisms controlling this interaction, especially within the context of FR regulation and folate status, have remained obscure. Human cervical carcinoma cells exhibited progressively increasing upregulation of FRs after shifting of folate-replete cells to low-folate media, without a proportionate rise in FR mRNA or rise in hnRNP El. Translational FR upregulation was accompanied by a progressive accumulation of the metabolite homocysteine within cultured cells, which stimulated interaction of the FR mRNA cis-element and hnRNP E 1 as well as FR biosynthesis in a dose-dependent manner. Abrupt reversal of folate deficiency also led to a rapid parallel reduction in homocysteine and FR biosynthesis to levels observed in folate-replete cells. Collectively, these results suggest that homocysteine is the key modulator of translational upregulation of FRs and establishes the linkage between perturbed folate metabolism and coordinated upregulation of FRs.